Best Treatment Choice for Osteonecrosis of the Jaw (BETCON)

A Multicenter Randomized Controlled Open-label Trial of Conservative Management Versus Minimally Invasive Treatment With Leukocyte- and Platelet-rich Fibrin Versus Primary Surgery in Patients With Newly Diagnosed Osteonecrosis of the Jaw

BETCON is a pragmatic randomized controlled open-label multi-center study in patients with newly diagnosed stage I-II MRONJ designed to answer the question whether minimally invasive management with LPRF membranes or primary surgical treatment is better than the standard of care of conservative therapy alone. The primary end-point is the time to mucosal healing. Secondary end-points consist of supporting measures of efficacy, patient reported symptoms, quality of life, well-being, and functioning.

Study Overview

• Status: Recruiting
• Conditions: Medication Related Osteonecrosis of the Jaw
• Intervention / Treatment: Drug: Antibiotics; Drug: Chlorhexidine mouthwash; Procedure: Minimally invasive surgery with LPRF; Procedure: Surgical resection

Detailed Description

While effective for symptom control and well tolerated, conservative treatment of MRONJ yields highly variable mucosal healing rates ranging between 20 to 50%. In an effort to improve these suboptimal outcomes, many adjunct treatment modalities have been studied, of which the use of minimally invasive surgery with autologous platelet rich plasma (LPRF) to improve wound healing has attracted considerable attention, with reported mucosal closure rates of up to 86% in single arm case series. More recently, improved understanding of the need for pre-operative infection control and adaptation of surgical protocols has renewed the interest in the primary surgical treatment of MRONJ with mucosal closure achieved in up to 90% of patients in some case series.

Therapeutic studies of MRONJ have almost exclusively focused on mucosal healing as the desired end-point of MRONJ treatment, with little or no attention to patient symptoms, quality of life, functioning and well-being during treatment, even though the resolution of MRONJ symptoms and limiting treatment related adverse events may be equally important to patients.

This comparative effectiveness research (CER) study is a randomized controlled open-label multi-center study in patients with newly diagnosed stage I-II MRONJ and is designed to answer the question whether minimally invasive treatment with LPRF membranes or primary surgical treatment improves outcomes when added to the standard of care of conservative treatment alone. The study also incorporates pragmatic design elements and uses patient reported outcomes (PRO) to determine which treatment offers the best humanistic outcomes considering both efficacy and measures of quality of life, functioning, well-being and symptom control. Indeed, this study will not use an investigational new drug (or drug regimen), device, or surgical technique, but rather evaluate their relative efficacy to guide future clinical management. Finally, plasma and saliva will be collected to identify prognostic and predictive biomarkers of outcome.

• Study Type: Interventional
• Enrollment (Anticipated): 125
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tim Van den Wyngaert, MD, PhD; Phone Number: 003238213568; Email: tim.van.den.wyngaert@uza.be

Study Locations

• Belgium
  • Antwerp, Belgium, 2020
    • Recruiting
    • ZNA Middelheim
    • Contact: Olivier Lenssen, MD, DDS
  • Edegem, Belgium, 2650
    • Recruiting
    • Antwerp University Hospital
    • Contact: Tim Van den Wyngaert, MD, PhD
  • Leuven, Belgium, 3000
    • Recruiting
    • UZ Leuven
    • Contact: Constantinus Politis, MD, DDS, PhD
  • Sint Niklaas, Belgium, 9100
    • Recruiting
    • AZ Nikolaas
    • Contact: Vincent Lenaerts, MD, DDS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• >18 years of age
• Provision of signed informed consent
• A history of at least one administration of, or an ongoing treatment with, a bone modifying agent in dose registered for the prevention of skeletal related events in bone metastatic disease or multiple myeloma
• Diagnosis of stage I-II MRONJ according to AAOMS 2014 criteria not more than 8 weeks prior to the date of screening

Exclusion criteria:

• Any prior treatment for MRONJ other than local antiseptic rinses, systemic antibiotics, or analgesics
• Prior radiotherapy to the head and neck region
• Medical contraindication to receive any of the possible study treatments
• Stage III MRONJ characterized by very extensive bone necrosis, pathological fracture, or fistulas to the skin or sinuses
• Multiple MRONJ lesions that cannot be closed in a single surgical procedure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Conservative treatment; Amoxicillin-based antibiotics and chlorhexidine oral rinse. Minor debridement. Primary wound closure is not part of this treatment strategy.	Drug: Antibiotics; Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication; Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication; Amoxicillin 1g bid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.; Other Names: amoxicillin; Drug: Chlorhexidine mouthwash; Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.; Other Names: chlorhexidine
Experimental: Minimally invasive approach + LPRF; Amoxicillin-based antibiotics and chlorhexidine oral rinse. Minimally-invasive surgical treatment, including sequestrectomy, debridement of soft tissue, and application of LPRF membranes before tension-free wound closure is obtained. Marginal resection of all necrotic bone is not part of this treatment strategy.	Drug: Antibiotics; Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication; Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication; Amoxicillin 1g bid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.; Other Names: amoxicillin; Drug: Chlorhexidine mouthwash; Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.; Other Names: chlorhexidine; Procedure: Minimally invasive surgery with LPRF; Minimally-invasive surgical treatment, including sequestrectomy, debridement of soft tissue, and application of LPRF membranes before tension-free wound closure is obtained. Marginal resection of all necrotic bone is not part of this treatment strategy.
Experimental: Primary surgical management; Amoxicillin-based antibiotics and chlorhexidine oral rinse. Removal of the necrotic bone without excessive resection of healthy bone. Buccal mucoperiosteal flaps will be used to achieve a tension-free mucosal coverage.	Drug: Antibiotics; Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication; Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication; Amoxicillin 1g bid PO Penicillin contra-indication or intolerance; Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.; Other Names: amoxicillin; Drug: Chlorhexidine mouthwash; Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.; Other Names: chlorhexidine; Procedure: Surgical resection; Primary surgical management consisting of the removal of the necrotic bone without excessive resection of healthy bone. Buccal mucoperiosteal flaps will be used to achieve a tension-free mucosal coverage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to confirmed mucosal healing	Time after randomization until the observation of healed mucosa (without presence of surgical suturing material) at the site of MRONJ, with a first observation of healed mucosa requiring confirmation after 4 weeks.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucosal closure	Proportion of patients with mucosal closure 6 months after randomization	6 months
Time to MRONJ healing	Time to resolution of MRONJ symptoms after start of treatment	12 months
Relapse rate of MRONJ	Incidence of patients with relapse at the site of MRONJ	12 months
Antibiotics use	Total duration of exposure to antimicrobial agents	12 months
Evolution of cancer health-related quality-of-life	Changes over time as measured with the EORTC QLQ-C30 questionnaire.	12 months
Evolution of general health status	Changes over time as measured with the EUROQOL 5D (EQ-5D-5L) questionnaire.	12 months
Evolution of oral health-specific quality-of-life	Changes over time as measured with the Oral Health Impacts Profile (OHIP-14) and the SWOG0702 Oral Health and Oral Health-related Quality of Life questionnaires.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment related adverse events	Incidence and intensity of treatment emergent adverse events	Through study completion, an average of 1 year
Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST)	This analysis analysis considers three health states: toxicity, time without symptoms and toxicity (TWiST), and relapse. The toxicity state comprises the total time after randomization and before relapse of MRONJ symptoms spent with toxicity, regardless of when the toxicity started or gaps between toxicities. The TWiST state is defined as the time of relapse of MRONJ symptoms minus time with toxicities. The duration of the relapse state is defined as overall survival time minus time to relapse of MRONJ symptoms.	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Tim Van den Wyngaert
• Collaborators: Kom Op Tegen Kanker
• Investigators: Principal Investigator: Tim Van den Wyngaert, MD, PhD, University Hospital, Antwerp

Publications and helpful links

General Publications

• Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O, Peter JU. Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev. 2022 Jul 12;7(7):CD012432. doi: 10.1002/14651858.CD012432.pub3.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Anticipated): October 1, 2025
• Study Completion (Anticipated): January 1, 2026

Study Registration Dates

• First Submitted: August 8, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 20, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Musculoskeletal Diseases; Bone Diseases; Osteonecrosis; Anti-Infective Agents, Local; Anti-Infective Agents; Dermatologic Agents; Disinfectants; Anti-Bacterial Agents; Chlorhexidine; Amoxicillin; Chlorhexidine gluconate
• Other Study ID Numbers: 2018/11482/1; 338 (EDGE)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No